Kif3a constrains β-catenin-dependent Wnt signalling through dual ciliary and non-ciliary mechanisms

Corbit, Kevin C.; Shyer, Amy E.; Dowdle, William E.; Gaulden, Julie; Singla, Veena; Reiter, Jeremy F.

doi:10.1038/ncb1670

Cited by 470 publications

(477 citation statements)

References 32 publications

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“…We have shown previously that suppression of some BBS proteins in zebrafish causes gastrulation defects that include shortened body axes, longer somites, and broad and kinked notochords (14,16,17,20,21). These phenotypes are consistent with abnormal planar cell polarity (PCP) signaling (21,22,24,25), which likely underlies several clinical phenotypes in patients who have BBS, including hearing defects (20), neural tube closure abnormalities (26), renal cyst formation (27), and possibly obesity and cognitive impairment (28). The fact that these observations are likely relevant to the etiopathology of BBS (20,21,(23)(24)(25), and true for all seven bbs orthologues tested (bbs1, bbs4, bbs6, bbs10, bbs12, mks1, and cep290) as well for as the three BBS modifiers mgc1203, mks3, and rpgrip1l, suggested that they might represent useful assays for all BBS genes.…”

Section: Resultssupporting

confidence: 49%

“…These phenotypes are consistent with abnormal planar cell polarity (PCP) signaling (21,22,24,25), which likely underlies several clinical phenotypes in patients who have BBS, including hearing defects (20), neural tube closure abnormalities (26), renal cyst formation (27), and possibly obesity and cognitive impairment (28). The fact that these observations are likely relevant to the etiopathology of BBS (20,21,(23)(24)(25), and true for all seven bbs orthologues tested (bbs1, bbs4, bbs6, bbs10, bbs12, mks1, and cep290) as well for as the three BBS modifiers mgc1203, mks3, and rpgrip1l, suggested that they might represent useful assays for all BBS genes. We therefore designed translation-blocking morpholinos (MOs) against bbs1-12 ( and SI Appendix, Table S1) and injected each into WT embryos at varying concentrations to establish a survival curve (SI Appendix, Table S3) from which to derive the optimal working MO concentration (minimal cytotoxicity, maximal phenotype).…”

Section: Resultsmentioning

confidence: 86%

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Functional analyses of variants reveal a significant role for dominant negative and common alleles in oligogenic Bardet–Biedl syndrome

Zaghloul

Liu

Gerdes

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

109

145

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Technological advances hold the promise of rapidly catalyzing the discovery of pathogenic variants for genetic disease. However, this possibility is tempered by limitations in interpreting the functional consequences of genetic variation at candidate loci. Here, we present a systematic approach, grounded on physiologically relevant assays, to evaluate the mutational content (125 alleles) of the 14 genes associated with Bardet-Biedl syndrome (BBS). A combination of in vivo assays with subsequent in vitro validation suggests that a significant fraction of BBS-associated mutations have a dominantnegative mode of action. Moreover, we find that a subset of common alleles, previously considered to be benign, are, in fact, detrimental to protein function and can interact with strong rare alleles to modulate disease presentation. These data represent a comprehensive evaluation of genetic load in a multilocus disease. Importantly, superimposition of these results to human genetics data suggests a previously underappreciated complexity in disease architecture that might be shared among diverse clinical phenotypes.epistasis | ciliopathy | zebrafish | in vivo assays E xome and whole-genome resequencing is likely to catalyze a paradigm shift in the identification of genetic lesions in patients (1). At the same time, even within the confines of the coding genome, such technologies pose an interpretive problem, in that the pathogenic candidacy of mutations can only be derived by narrow genetic models and limited computational predictive tools, both of which are likely to under-and misinterpret the effect of some mutations. Moreover, inter-and intrafamilial variability, a phenomenon prevalent in most genetic traits, remains a major confounding factor because both allelic variation at a single locus and second-site trans modifiers can exert a significant influence on penetrance and expressivity through additive and epistatic effects (2).Bardet-Biedl Syndrome (BBS) is a useful model for dissecting epistasis because most of the 14 BBS genes can also contribute epistatic alleles (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). BBS is also a representative of the ciliopathy disease spectrum, a group of disorders characterized by defects in ciliary structure and/or ciliary signal output (18). Hallmarks of BBS include retinal degeneration, obesity, hypogonadism, polydactyly, renal dysfunction, and mental retardation (19).We and others have shown that the zebrafish provides experimentally tractable and physiologically relevant models of important aspects of ciliary dysfunction (2,15,17,(20)(21)(22)(23). Moreover, human mRNA for ciliopathy genes can rescue both morphant and mutant zebrafish phenotypes efficiently, providing a robust platform for interpretation of the pathological relevance of identified missense alleles, whose causal relation to the disorder cannot be proven definitively with genetic arguments alone (15,17,22,23).Here, we have integrated multiple independent in vivo assays, followed by in vitro validations, to int...

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Section: Resultssupporting

confidence: 49%

Section: Resultsmentioning

confidence: 86%

Functional analyses of variants reveal a significant role for dominant negative and common alleles in oligogenic Bardet–Biedl syndrome

Zaghloul

Liu

Gerdes

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

109

145

View full text Add to dashboard Cite

show abstract

“…Mechanistically, conditional loss of Kif3a and IFT in the developing mouse cerebellum results in the failure of Shhdependent proliferation of granule neuron progenitors within the developing cerebellar external granule layer [44,45] (Figure 1B). Since cilia are required to process both Shh and Wnt signals in a range of cell types [46][47][48][49], it is hypothesized that the JSRD genes encode mediators of these signal transduction pathways at the primary cilium and that the primary defect in JSRD is compromised granule cell proliferation which in turn, leads to significant cerebellar hypoplasia. Axonal migration defects causing the distinctive "molar tooth" sign may also be caused by ciliary defects, however, until JSRD gene-specific knock-outs are available, these hypotheses cannot be directly tested.…”

Section: Joubert Syndrome and Related Disordersmentioning

confidence: 99%

Cerebellar development and disease

Millen¹,

Gleeson²

2008

Current Opinion in Neurobiology

171

141

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The molecular control of cell type specification within the developing cerebellum as well as the genetic causes of the most common human developmental cerebellar disorders have long remained mysterious. Recent genetic lineage and loss-of-function data from mice have revealed unique and non-overlapping anatomical origins for GABAergic neurons from ventricular zone precursors and glutamatergic cell from rhombic lip precursors, mirroring distinct origins for these neurotransmitterspecific cell types in the cerebral cortex. Mouse studies elucidating the role of Ptf1a as a cerebellar ventricular zone GABerigic fate switch were actually preceded by the recognition that PTF1A mutations in humans cause cerebellar agenesis, a birth defect of the human cerebellum. Indeed, several genes for congenital human cerebellar malformations have recently been identified, including genes causing Joubert syndrome, Dandy-Walker malformation and Ponto-cerebellar hypoplasia. These studies have pointed to surprisingly complex roles for transcriptional regulation, mitochondrial function and neuronal cilia in patterning, homeostasis and cell proliferation during cerebellar development. Together mouse and human studies are synergistically advancing our understanding of the developmental mechanisms that generate the uniquely complex mature cerebellum.

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“…By contrast, OFD1 acts at the distal ends of centrioles to control distal appendage formation and centriole length [126]. It is involved in targeting the IFT protein, IFT88, to the distal end of the centriole and possibly to the basal body [127]. Through recruitment of CEP164, a distal appendage protein mutated in cystic kidney disease, OFD1 also promotes basal body docking to the plasma membrane [114,128].…”

Section: Ciliopathies (A) Primary Cilia Formation and Centriolar Satementioning

confidence: 99%

Small organelle, big responsibility: the role of centrosomes in development and disease

Chavali

Pütz

Gergely

2014

Phil. Trans. R. Soc. B

140

111

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The centrosome, a key microtubule organizing centre, is composed of centrioles, embedded in a protein-rich matrix. Centrosomes control the internal spatial organization of somatic cells, and as such contribute to cell division, cell polarity and migration. Upon exiting the cell cycle, most cell types in the human body convert their centrioles into basal bodies, which drive the assembly of primary cilia, involved in sensing and signal transduction at the cell surface. Centrosomal genes are targeted by mutations in numerous human developmental disorders, ranging from diseases exclusively affecting brain development, through global growth failure syndromes to diverse pathologies associated with ciliary malfunction. Despite our much-improved understanding of centrosome function in cellular processes, we know remarkably little of its role in the organismal context, especially in mammals. In this review, we examine how centrosome dysfunction impacts on complex physiological processes and speculate on the challenges we face when applying knowledge generated from in vitro and in vivo model systems to human development.

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Kif3a constrains β-catenin-dependent Wnt signalling through dual ciliary and non-ciliary mechanisms

Cited by 470 publications

References 32 publications

Functional analyses of variants reveal a significant role for dominant negative and common alleles in oligogenic Bardet–Biedl syndrome

Functional analyses of variants reveal a significant role for dominant negative and common alleles in oligogenic Bardet–Biedl syndrome

Cerebellar development and disease

Small organelle, big responsibility: the role of centrosomes in development and disease

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